WJN
World Journal of Nephrology
Online Submissions: http://www.wjgnet.com/esps/ [email protected] doi:10.5527/wjn.v3.i2.16
World J Nephrol 2014 May 6; 3(2): 16-23 ISSN 2220-6124 (online)
© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
s
MINIREVIEWS
Pediatric lupus nephritis: Management update Rajiv Sinha, Sumantra Raut Rajiv Sinha, Division of Pediatric Nephrology, Department of Pediatrics, Institute of Child Health, Kolkata 700017, India Sumantra Raut, Department of Pediatrics, Dr B C Roy Post Graduate Institute of Pediatric Sciences, Kolkata 700054, India Author contributions: Sinha R designed the study; Raut S performed the search; Sinha R and Raut S wrote the paper. Correspondence to: Dr. Rajiv Sinha, MD, FRCPCH (UK) (CCT, UK), Division of Pediatric Nephrology, Department of Pediatrics, Institute of Child Health, 11 Biresh Guha Street, Kolkata 700017, India. [email protected] Telephone: +91-93-30819380 Fax: +91-33-22801525 Received: May 30, 2013 Revised: August 28, 2013 Accepted: March 3, 2014 Published online: May 6, 2014
tosus (cSLE) is a rare but severe autoimmune disease with multisystem involvement. Renal disease occurs in 50% to 75% of all cSLE patients and is a major cause of increased morbidity and mortality. Originally SLE nephritis was treated with steroids with a poor outcome which improved markedly with the introduction of cyclophosphamide, but at the cost of increased side effects which resulted in a further search for a less toxic, but equally effective regime. Here we discuss some newer drugs including immune-modulators and monoclonal antibodies in addition to azathioprine and mycophenolate mofetil, however, most of the evidence on these medications is restricted to adult literature and pediatric data are extrapolated from these trials.
Abstract
Sinha R, Raut S. Pediatric lupus nephritis: Management update. World J Nephrol 2014; 3(2): 16-23 Available from: URL: http:// www.wjgnet.com/2220-6124/full/v3/i2/16.htm DOI: http:// dx.doi.org/10.5527/wjn.v3.i2.16
Childhood-onset systemic lupus erythematosus (cSLE) is a severe multisystem autoimmune disease. Renal involvement occurs in the majority of cSLE patients and is often fatal. Renal biopsy is an important investigation in the management of lupus nephritis. Treatment of renal lupus consists of an induction phase and maintenance phase. Treatment of childhood lupus nephritis using steroids is associated with poor outcome and excess side-effects. The addition of cyclophosphamide to the treatment schedule has improved disease control. In view of treatment failure using these drugs and a tendency for non-adherence, many newer agents such as immune-modulators and monoclonal antibodies are being tried in patients with cSLE. Trials of these novel agents in the pediatric population are still lacking making a consensus in the management protocol of pediatric lupus nephritis difficult.
INTRODUCTION Epidemiology Childhood-onset systemic lupus erythematosus (cSLE) is a rare but severe autoimmune disease with multisystem involvement, the incidence is 0.3/100000-0.9/100000 children-per year with a prevalence of 3.3/100000-8.8/100000 children[1]. A higher frequency of cSLE is reported in Asians, African Americans, Hispanics, and native Americans[2]. Median age of onset of cSLE is between 11 and 12 years (rare below 5 years), and 80% of patients are female[3]. cSLE follows a more severe disease course than adult-onset SLE, with higher morbidity and lower survival rates[4].
© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
Diagnosis of cSLE Four out of 11 American College of Rheumatology (ACR) criteria have a sensitivity and specificity greater than 95% for the diagnosis of cSLE. These criteria are as follows: malar rash, discoid rash, photosensitivity rash, oral or nasopharyngeal ulceration, nonerosive arthritis,
Key words: Pediatric; Lupus nephritis; Management; Monoclonal antibody; Cyclophosphamide; Mycophenolate mofetil Core tip: Childhood-onset systemic lupus erythema-
WJN|www.wjgnet.com
16
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis [11,12]
Table 1 International society of nephrology/renal pathology society 2003 classification of lupus nephritis Class
Name Minimal mesangial LN Mesangial proliferative LN
I II III
Focal LN
IV
Diffuse LN
V VI
A Active lesions A/C Active and chronic lesions C Chronic lesions A Active lesions A/C Active and chronic lesions C Chronic lesions Membranous LN Advanced sclerosing LN
Light microscopy
Immunofluorescence
Normal Mesangial immune deposits Mesangial hypercellularity or mesangial Mesangial immune deposits matrix expansion Segmental, or global glomerulonephritis Diffuse subendothelial immune deposits (< 50% of glomeruli) Segmental, or global glomerulonephritis Diffuse subendothelial immune deposits LN (> 50% glomeruli) Global or segmental subepithelial immune deposits LN (> 90% globally Sclerosed glomeruli without residual activity)
Class V may occur in combination with class III or IV, in which case both will be diagnosed. LN: Lupus nephritis.
serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and antinuclear antibody[5]. Although still not widely used, the newer systemic lupus international collaborating clinics (SLICC) criteria have been introduced for the classification of SLE[6]. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-doublestranded DNA antibodies.
INDICATIONS FOR RENAL BIOPSY IN PATIENTS WITH CSLE[12] Increased serum creatinine without compelling alternative causes, such as sepsis, hypovolemia, or medication. Confirmed proteinuria of 1.0 g per 24 h (either 24-h urine specimens or spot protein/creatinine ratios are acceptable). Combinations of the following, assuming the findings are confirmed in at least 2 tests performed within a short period of time and in the absence of alternative causes: (1) Proteinuria: 0.5 g per 24 h plus hematuria, defined as 5 RBCs per hpf; and (2) Proteinuria: 0.5 g per 24 h plus cellular casts. Renal biopsy should be reported as per the International Society of Nephrology/Renal Pathology classification (Table 1). Recent modifications of the activity and chronicity index not only help in acute management, but also help in prognostication.
Renal involvement Renal disease occurs in 50% to 75% of all cSLE patients, mostly within the first 2 years after diagnosis[7]. Lupus nephritis (LN) is more common in males and in nonWhite populations[8,9]. Initial manifestations of renal disease range from minimal proteinuria and microscopic hematuria to nephrotic-range proteinuria, urinary casts, severe hypertension, peripheral edema, and renal insufficiency or acute renal failure. SLE most commonly affects the glomerulus (i.e., lupus nephritis), but can also involve the renal interstitium. It can also present with features of thrombotic microangiopathy including both atypical hemolytic uremic syndrome as well as thrombotic thrombocytopenic purpura.
TREATMENT Originally SLE nephritis was treated by steroids with a poor outcome which improved markedly with the introduction of cyclophosphamide. The first controlled trial reporting the short-term efficacy of cyclophosphamide for lupus nephritis in adults was published in 1971[13]. Initially this combination was advocated for a prolonged period, but unfortunately the improved outcome was found to be associated with long-term side effects, which resulted in a further search for a less toxic, but equally effective regime. Most of the studies have been performed in adults and to a large extent the current recommendations are borrowed heavily from adult studies. The current therapeutic strategy for SLE nephritis distinguishes two distinct phases of treatment. The first phase is INDUCTION therapy which aims to control disease activity by inducing remission of disease flare (which may be the initial presentation or represent a new flare). It is at this point that potential organ-threatening and/or life-
CASE DEFINITION FOR LN As per the ACR criteria, LN is defined as: persistent proteinuria i.e., 0.5 g per day [a spot urine protein/creatinine ratio of 0.5 can be substituted) or greater than 3+ by dipstick; and/or cellular casts including red blood cells (RBCs), granular, tubular, or mixed][10]. An additional, perhaps optimal, criterion is a renal biopsy sample demonstrating immune complex-mediated glomerulonephritis compatible with LN[11]. As the severity of the nephritis may not correlate with the severity of the clinical signs and symptoms, a renal biopsy should be performed for any suspicion of glomerulonephritis, including persistent mild proteinuria.
WJN|www.wjgnet.com
17
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
threatening disease needs to be aggressively treated. The second phase is MAINTENANCE, wherein the target is to avoid relapses and control the disease by limiting inflammation and damage. Class Ⅰ/Ⅱ LN are milder and generally do not require immunosuppressive treatment, whereas class Ⅲ /Ⅳ needs to be treated aggressively[14]. Research studies over the last decade have shown increasing evidence of the efficacy of mycophenolate mofetil (MMF)/azathioprine (AZA) with a better side effect profile as compared to cyclophosphamide (CyC). Despite this, as shown by the recently conducted consensus meeting of pediatric rheumatologists and nephrologists in North America, the majority still prefer CyC as the induction agent[15]. Most of the studies on the use of MMF in children have only been case series. The largest series included 31 children or young people who were treated with MMF (either initially or switched from AZA) and showed that 73% had a good response without any recorded major side-effects [16]. Among the multiple adult studies, the first comparative study on MMF compared with CyC was published in Hong Kong in 2000[17]. MMF and CyC showed similar rates of improvement and of complete remission, 81% and 76%, respectively. Patients experienced fewer sideeffects with MMF treatment. Subsequently Contreras et al[18], studied 59 adults with lupus nephritis who were initially treated with 4-7 mo infusions of CyC and then randomized to quarterly infusions of CyC or oral MMF or AZA. Patients treated with AZA or MMF showed fewer flares than those treated with CyC, six, three, and eight flares, respectively. Patients treated with MMF experienced fewer side-effects than those treated with CyC except for an increased risk of gastrointestinal symptoms and diarrhea with MMF. To date, the biggest study, the aspreva lupus management study (ALMS) attempted to determine the efficacy of MMF as an induction agent for LN. The study included 370 patients with class Ⅲ through Ⅴ lupus nephritis[19] and consisted of one 24-wk induction phase and thereafter a 3-year maintenance phase. The results did not show any difference between the percentages of patients responding to treatment (56.2% in the MMF group, and 53.0% in the CyC group). There was also no significant difference in the rate of side-effects and a tendency for more severe adverse events in the MMF group (P = 0.07). In a sub-analysis of the ALMS, Isenberg et al[20] showed that response varied with race, in that Black and Hispanic patients responded better to MMF (60.4%) compared to CyC (38.5%), P = 0.03. In a recently published meta-analysis, Touma et al[21] looked at the cumulative evidence for MMF/CyC as induction treatment. Four trials with 668 patients were included and no difference in clinical efficacy was found between the two drugs. MMF did, however, show significantly less alopecia (RR = 5.77; 95%CI: 1.56-21.38), but other side-effects were not significantly different. Researchers have also studied patients with class Ⅴ nephritis (i.e., a membranous pattern on kidney biopsy) and found no differences between the MMF and CyC-treated groups[22]. Based on these studies, the ACR has published their recommendation on
WJN|www.wjgnet.com
SLE nephritis, albeit targeted primarily towards the adult population. ACR recommendation As per the ACR recent recommendation for class Ⅲ/Ⅳ LN, MMF and glucocorticoids (GC) can be used as induction agents for African-American and Hispanic patients, whereas Cyc and GC remain the first choice for White populations. MMF and GC are agents of choice in isolated class Ⅴ LN[10]. In mixed cases such as class V with Ⅲ or Ⅳ LN, the treatment should be similar to that for class Ⅲ/Ⅳ LN. Other induction modalities that can be tried in refractory cases include intravenous immunoglobulin, plasma exchange and B-lymphocyte depletion agents such as Rituximab[23,24] (Figures 1 and 2). The ACR recommends either MMF or AZA and low dose steroid for the maintenance phase. MMF has been shown to be statistically better than AZA in terms of time to treatment failure (a composite including death, end stage renal disease, doubling of serum creatinine, and renal flare)[25]. In patients who fail to respond after 6 mo of treatment with GC plus MMF or CyC, the ACR recommend a switch of immunosuppressive agent from either CyC to MMF or from MMF to CyC, and these changes are accompanied by Ⅳ pulses of GCs. Adherence Non-adherence to immunosuppressive agents can be common in the adolescent age group[14], resulting in relapse of symptoms and sometimes an acute presentation with renal failure after initial successful treatment. Intravenous agents, such as CyC or rituximab can be considered in this situation, to ensure adherence and disease control.
RECENT ADVANCES IN SLE MEDICATIONS Despite advances in treatment, mortality related to SLE nephritis has been static over the last decade and morbidity continues to be a major factor. Hence, there is a strong need for more effective drugs with, if possible, fewer side-effects. Studies are particularly required in children, as due to a lack of pediatric studies drugs trialed on adults are still been tried in children with severe lupus nephritis. We will discuss some of the newer medicines, however, most of the evidence on these medications is restricted to adult literature. Rituximab Rituximab, a chimeric antibody targeting CD20-positive cells, was first used by Tullus[26] in 2000 in a girl with class Ⅴ lupus nephritis and therapy-resistant nephrotic syndrome. The therapeutic response was remarkable and her proteinuria improved so much that her serum albumin normalized. Many other clinicians have had similar clinical experiences and several case series have published positive results[14,27]. Unfortunately the first randomized
18
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
MMF 2-3 g/d × 6 mo (preferred to CYC in Hispanics and African American) plus GC i.v. pulse × 3 d then prednisolone 0.5-1.0 mg/kg per day, tapered after a few weeks to lowest effective dose (1 mg/kg per day if crescent seen)
CYC plus GC i.v. pulse × 3 d then prednisolone 0.5-1 mg/kg per day, tapered after a few weeks to lowest effective dose (1 mg/kg per day if crescent seen)
or
Low dose CYC 500 mg i.v. every 2 wk × 6 mo Followed by maintenance with oral MMF or AZA (White European)
6 mo
or
High dose CYC 2 500-1000 mg/m BSA i.v. every month × 6
Not improved
Improved
6 mo Improved MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
Improved
Maintenance MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
CYC (low/high) + pulse GC then daily GC
Not improved
MMF 1-2 g/d or AZA 2 mg/kg per day +/low dose daily GC
Not improved
Improved
Maintenance MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
Rituximab or calcineurin inhibitors + GC
MMF 2-3 g/d × 6 mo + Pulse GC then daily GC
Not improved
Rituximab or calcineurin inhibitors + GC
Figure 1 Class Ⅲ/Ⅳ lupus nephritis induction therapy. MMF: Mycophenolate mofetil; CYC: Cyclophosphamide; GC: Glucocorticoids; iv: Intravenous; AZA: Azathioprine; BSA: Body surface area.
ing. A phase Ⅲ randomized double-blind placebo controlled study showed significant benefit, but to date, there is not enough data to recommend its use in children with lupus nephritis[31].
controlled trial, EXPLORER, which included 237 patients with moderate to severe extra-renal lupus did not find any difference between rituximab and placebo[28]. Another large randomized placebo-controlled study on rituximab, the LUNAR trial[29], which included 144 patients with class Ⅲ or Ⅳ lupus nephritis showed that only 30.6% of the patients in the placebo group and 25.4% of the rituximab-treated patient fulfilled the criteria for a complete response. Greater improvements in complement levels (P = 0.025) and antibodies to dsDNA (P = 0.007) were recorded in the rituximab group compared to the placebo group[30].
Ocrelizumab Ocrelizumab is a fully humanized antibody that targets CD20-positive B cells. It is a “next-generation rituximab” and the potential problem of human anti-chimeric antibody development is hopefully ameliorated. The BELONG study, 2010 was set up to study the efficacy of ocrelizumab in 381 patients with lupus nephritis[32] and the results are awaited.
Belimumab Belimumab is a fully humanized monoclonal antibody that binds to soluble B-lymphocyte stimulator (BLyS) and acts as a specific inhibitor of its biological activity. BLyS, also known as B-cell activating factor (BAFF) is an immunomodulatory cytokine that promotes B-cell survival, B-cell differentiation, and immunoglobulin class switch-
WJN|www.wjgnet.com
Epratuzumab Epratuzumab is a monoclonal antibody against CD22, another B-cell-specific surface antigen. Early open data in a few patients have shown positive results[33]. A study involving 227 patients found that a dose of 600 mg weekly was associated with greater british isles lupus activity
19
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis Figure 2 Treatment of class Ⅴ without proliferative changes and with nephrotic range proteinuria (> 3 g/24 h). MMF: Mycophenolate mofetil; AZA: Azathioprine; CYC: Cyclophosphamide; GC: Glucocorticoids.
MMF 2-3 g/d × 6 mo plus prednisolone 0.5-1 mg/kg per day × 6 mo
Improved
Not improved
2
MMF 1-2 g/d or AZA 2 mg/kg per day
CYC 500-1000 mg/m BSA i.v. every month × 6 plus GC pulse followed by prednisolone 0.5-1.0 mg/kg per day
Table 2 Monitoring schedule for systemic lupus erythematosus nephritis Stage of disease Active nephritis at onset of treatment Previous active nephritis, none currently No prior or current nephritis
Blood pressure
Urinalysis
1 3 3
1 3 6
Protein/creatinine ratio Serum creatinine 1 3 6
grading improvement[34].
C3/C4 level
Anti-DNA
2 3 6
3 6 6
1 3 6
Index scores (Safety of estrogens in lupus erythematosus national assessment) were given three infusions of two different doses of rigerimod or placebo followed by 12 wk of observation. The treatment seemed to be well tolerated and a statistically significant reduction in disease activity was recorded[38]. Longer-term studies are needed.
Tocilizumab Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor. In a phase Ⅰ study of 16 patients with mild to moderate lupus, tocilizumab was found to be well tolerated, significantly reducing plasma cells and dsDNA suggesting a good clinical response[35]. Further studies seem warranted.
Abatacept Abatacept is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7 which selectively modulates the CD80/CD86:CD28 co-stimulatory signal. A recent 12-mo double-blind placebo-controlled study in 118 lupus patients failed to meet the primary end point of a reduction in new flares[39]. Serious adverse events were higher in the abatacept group compared with the placebo group (20% vs 7%).
Abetimus Abetimus is an immunomodulating agent designed to induce tolerance in B cells directed against dsDNA and to reduce anti-dsDNA levels. It is a synthetic molecule consisting of four double-stranded oligodeoxyribonucleotides attached to non-immunogenic polyethylene glycol. Abetimus works through the formation and clearance of drug antibody complexes and by tolerating anti-dsDNA specific B cells. Cardiel et al[36], 2008 in a 22-mo study of 317 patients showed that abetimus failed to prolong time to flare compared to the placebo.
Infliximab The use of infliximab in lupus has been surrounded with major worries. Long-term use of infliximab in lupus patients can cause severe side-effects, including severe infections and even cerebral lymphoma[40].
Atacicept Atacicept is a receptor analogue that binds both BAFF and a proliferation-inducing ligand to related members of the tumor necrosis factor superfamily. A phase Ⅱ study of atacicept showed a marked reduction in B cells and immunoglobulin levels and a short term side-effect profile similar to placebo[37].
ADJUNCTIVE TREATMENTS The ACR recommended that all SLE patients with nephritis be treated with a background of hydroxychloroquine (HCQ), unless there is a contraindication [11]. HCQ treatment may reduce the risk of renal damage and clotting events in SLE[41-43]. Medications to control high blood pressure (anti-hypertensive), fluid overload (diuretics), proteinuria (angiotensin converting enzyme inhibitors), hypercoagulability (aspirin or other anticoagulants) and lipid control (statins)[22,44,45] are mainstays of adjunc-
Rigeromid Rigerimod is a spliceosomal peptide that is recognized by CD4+ T cells from patients with lupus, but not from those with other autoimmune diseases. In a 12-wk study, 150 patients with lupus and high SLE Disease Activity
WJN|www.wjgnet.com
[10]
20
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
tive treatment. Dietary restriction may be necessary in terms of sodium, protein and calories. Unlike adults, these recommendations must be adjusted to take into account the growth and developmental status of the child. Infection is the most common cause of death in cSLE due to immune suppression[46]. Infections can be difficult to differentiate from a flare of SLE disease activity. C-reactive protein monitoring can be useful as most SLE patients have normal levels, except during inter-current infections.
7 8
RECOMMENDED MONITORING OF LUPUS NEPHRITIS
9
SLE is a chronic disease with the possibility of frequent flare-ups. Hence, these children need to be followed up regularly (Table 2). Compliance can be a major issue and needs to be addressed during each clinic visit[47].
10 11
CONCLUSION In conclusion, the outcome of lupus nephritis is primarily dependent on histological classification at presentation. Early renal biopsy in all children with features of lupus nephritis to decide on induction therapy, aggressive treatment of hypertension and other adjunct therapy is recommended to improve mortality and morbidity of such patients.
12
REFERENCES 1
2
3
4
5
6
Kamphuis S, Silverman ED. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol 2010; 6: 538-546 [PMID: 20683438 DOI: 10.1038/ nrrheum.2010.121] Malleson PN, Fung MY, Rosenberg AM. The incidence of pediatric rheumatic diseases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 1996; 23: 1981-1987 [PMID: 8923379] Huang JL, Yao TC, See LC. Prevalence of pediatric systemic lupus erythematosus and juvenile chronic arthritis in a Chinese population: a nation-wide prospective populationbased study in Taiwan. Clin Exp Rheumatol 2004; 22: 776-780 [PMID: 15638056] Baqi N, Moazami S, Singh A, Ahmad H, Balachandra S, Tejani A. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol 1996; 7: 924-929 [PMID: 8793802] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725 [PMID: 9324032 DOI: 10.1002/art.1780400928] Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sánchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G, Magder LS. Derivation and validation of
WJN|www.wjgnet.com
13
14 15
16
17
18
21
the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677-2686 [PMID: 22553077 DOI: 10.1002/ art.34473] Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am 2012; 59: 345-364 [PMID: 22560574] Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, Urowitz M, Fortin PR, Petri M, Barr S, Gordon C, Bae SC, Isenberg D, Zoma A, Aranow C, Dooley MA, Nived O, Sturfelt G, Steinsson K, Alarcón G, Senécal JL, Zummer M, Hanly J, Ensworth S, Pope J, Edworthy S, Rahman A, Sibley J, El-Gabalawy H, McCarthy T, St Pierre Y, Clarke A, RamseyGoldman R. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2550-2557 [PMID: 16868977 DOI: 10.1002/art.21955] Alarcón GS, McGwin G, Petri M, Reveille JD, RamseyGoldman R, Kimberly RP. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002; 11: 95-101 [PMID: 11958584 DOI: 10.1191/9612332lu155oa] Dooley MA, Aranow C, Ginzler EM. Review of ACR renal criteria in systemic lupus erythematosus. Lupus 2004; 13: 857-860 [PMID: 15580982 DOI: 10.1191/0961203304lu2023oa] Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64: 797-808 [PMID: 22556106 DOI: 10.1002/acr.21664] Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241-250 [PMID: 14747370 DOI: 10.1097/01. ASN.0000108969.21691.5D] Steinberg AD, Kaltreider HB, Staples PJ, Goetzl EJ, Talal N, Decker JL. Cyclophosphamide in lupus nephritis: a controlled trial. Ann Intern Med 1971; 75: 165-171 [PMID: 4104337 DOI: 10.7326/0003-4819-75-2-165] Marks SD, Tullus K. Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr 2010; 99: 967-974 [PMID: 20222881] Mina R, von Scheven E, Ardoin SP, Eberhard BA, Punaro M, Ilowite N, Hsu J, Klein-Gitelman M, Moorthy LN, Muscal E, Radhakrishna SM, Wagner-Weiner L, Adams M, Blier P, Buckley L, Chalom E, Chédeville G, Eichenfield A, Fish N, Henrickson M, Hersh AO, Hollister R, Jones O, Jung L, Levy D, Lopez-Benitez J, McCurdy D, Miettunen PM, Quinterodel Rio AI, Rothman D, Rullo O, Ruth N, Schanberg LE, Silverman E, Singer NG, Soep J, Syed R, Vogler LB, Yalcindag A, Yildirim-Toruner C, Wallace CA, Brunner HI. Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2012; 64: 375-383 [PMID: 22162255 DOI: 10.1002/acr.21558.] Kazyra I, Pilkington C, Marks SD, Tullus K. Mycophenolate mofetil treatment in children and adolescents with lupus. Arch Dis Child 2010; 95: 1059-1061 [PMID: 20810399 DOI: 10.1136/adc.2009.178608] Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343: 1156-1162 [PMID: 11036121 DOI: 10.1056/NEJM200010193431604] Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis Nan P, Roth D. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350: 971-980 [PMID: 14999109 DOI: 10.1056/NEJMoa031855] 19 Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20: 1103-1112 [PMID: 19369404 DOI: 10.1681/ ASN.2008101028] 20 Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, Sánchez-Guerrero J, Wofsy D, Yu X, Solomons N. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010; 49: 128-140 [PMID: 19933596 DOI: 10.1093/rheumatology/ kep346] 21 Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011; 38: 69-78 [PMID: 20952473 DOI: 10.3899/ jrheum.100130] 22 Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos II, Appel GB. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int 2010; 77: 152-160 [PMID: 19890271 DOI: 10.1038/ki.2009.412] 23 Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, Bonnet C, Cacoub P, Cantagrel A, de Bandt M, Fain O, Fautrel B, Gaudin P, Godeau B, Harlé JR, Hot A, Kahn JE, Lambotte O, Larroche C, Léone J, Meyer O, PallotPrades B, Pertuiset E, Quartier P, Schaerverbeke T, Sibilia J, Somogyi A, Soubrier M, Vignon E, Bader-Meunier B, Mariette X, Gottenberg JE. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010; 62: 2458-2466 [PMID: 20506527 DOI: 10.1002/art.27541] 24 Wright EC, Tullus K, Dillon MJ. Retrospective study of plasma exchange in children with systemic lupus erythematosus. Pediatr Nephrol 2004; 19: 1108-1114 [PMID: 15300476 DOI: 10.1007/s00467-004-1552-7] 25 Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365: 1886-1895 [PMID: 22087680 DOI: 10.1056/NEJMoa1014460] 26 Tullus K. New developments in the treatment of systemic lupus erythematosus. Pediatr Nephrol 2012; 27: 727-732 [PMID: 21516516 DOI: 10.1007/s00467-011-1859-0] 27 Marks SD, Tullus K. Targeted B-cell depletion therapy in childhood-onset systemic lupus erythematosus: progress to date. Paediatr Drugs 2007; 9: 371-378 [PMID: 18052407] 28 Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010; 62: 222-233 [PMID: 20039413 DOI: 10.1002/art.27233] 29 Furie R, Looney J, Rovin B, Latinis KM, Appel G, SanchezGuerrero J, Fervenza F, Maciuca RD, Brunetta P, Zhang D, Garg J, the LUNAR study group. Efficacy and safety of rituximab in patients with proliferative lupus nephritis: results from the randomized, double-blind phase III LUNAR study 2010. 9th International Congress on Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 6 30 Furie R, Rovin BH, Appel G, Kamen DL, Fervenza FC, Spindler A, Maciuca R, Garg JP, Brunetta P, LUNAR Study Group. Effect of rituximab on anti-double-stranded DNA antibody and C3 levels and relationship to response: results from the LUNAR trial 2010. 9th International Congress on
WJN|www.wjgnet.com
31
32
33
34 35
36
37
38
39
40
41
42
22
Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 22 Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, Ginzler EM, D’Cruz DP, Doria A, Cooper S, Zhong ZJ, Hough D, Freimuth W, Petri MA. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 2012; 71: 1833-1838 [PMID: 22550315 DOI: 10.1136/annrheumdis-2011-200831.] Mysler E, Spindler A, Guzman R, Bijl M, Jayne D, Furie R, Maciuca R, Drappa J, Shahdad S, Close D. Study design and baseline patient characteristics of BELONG, the randomized double-blind, placebo-controlled phase III trial of ocrelizumab, a humanized anti-CD20 antibody, in lupus nephritis 2010. 9th International Congress on Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 20 Dörner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 2006; 8: R74 [PMID: 16630358 DOI: 10.1186/ar1942] Press release, UCB, Rome 16th 2010; Available from: URL: http://www.ucb.com/_up/ucb_com_news/document. Accessed 10 Nov 2012 Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, Fleisher T, Balow JE, Lipsky PE. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010; 62: 542-552 [PMID: 20112381 DOI: 10.1002/art.27221] Cardiel MH, Tumlin JA, Furie RA, Wallace DJ, Joh T, Linnik MD. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum 2008; 58: 2470-2480 [PMID: 18668592 DOI: 10.1002/art.23673] Pena-Rossi C, Nasonov E, Stanislav M, Yakusevich V, Ershova O, Lomareva N, Saunders H, Hill J, Nestorov I. An exploratory dose-escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus. Lupus 2009; 18: 547-555 [PMID: 19395457 DOI: 10.1177/0961203309102803] D’Andrea D, Xie F, Zimmer R. A randomized, doubleblind, placebo-controlled study of spliceosomal peptide rigerimod in patients with systemic lupus erythematosus (SLE), 2010. 9th Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P. The efficacy and safety of abatacept in patients with non-lifethreatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62: 3077-3087 [PMID: 20533545 DOI: 10.1002/art.27601] Aringer M, Houssiau F, Gordon C, Graninger WB, Voll RE, Rath E, Steiner G, Smolen JS. Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients. Rheumatology (Oxford) 2009; 48: 1451-1454 [PMID: 19748965 DOI: 10.1093/rheumatology/kep270] A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N Engl J Med 1991; 324: 150-154 [PMID: 1984192 DOI: 10.1056/ NEJM199101173240303] Fessler BJ, Alarcón GS, McGwin G, Roseman J, Bastian HM, Friedman AW, Baethge BA, Vilá L, Reveille JD. Systemic lupus erythematosus in three ethnic groups: XVI. Association
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
43
44
of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 2005; 52: 1473-1480 [PMID: 15880829 DOI: 10.1002/art.21039] Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, Lou W, Fortin PR. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010; 62: 863-868 [PMID: 20131232 DOI: 10.1002/art.27289] Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148: 30-48 [PMID: 17984482 DOI: 10.7326/0003-4819-148-1-200801010-00190]
45
Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y, Shen P, Chen N. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012; 27: 1467-1472 [PMID: 21917733 DOI: 10.1093/ndt/gfr484] 46 Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, MartinezBerriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009; 11: R109 [PMID: 19604357 DOI: 10.1186/ar2764] 47 Schmajuk G, Yazdany J. Drug monitoring in systemic lupus erythematosus: a systematic review. Semin Arthritis Rheum 2011; 40: 559-575 [PMID: 21030066 DOI: 10.1016/j.semarthri t.2010.07.010] P- Reviewers: Martins LSS, Pedersen EB, Sheashaa HA, Tanaka H S- Editor: Gou SX L- Editor: Webster JR E- Editor: Wu HL
WJN|www.wjgnet.com
23
May 6, 2014|Volume 3|Issue 2|
Published by Baishideng Publishing Group Co., Limited Flat C, 23/F., Lucky Plaza, 315-321 Lockhart Road, Wan Chai, Hong Kong, China Fax: +852-31158812 Telephone: +852-58042046 E-mail: [email protected] http://www.wjgnet.com
Baishideng Publishing Group Co., Limited
© 2014 Baishideng. All rights reserved.
World Journal of Nephrology
Online Submissions: http://www.wjgnet.com/esps/ [email protected] doi:10.5527/wjn.v3.i2.16
World J Nephrol 2014 May 6; 3(2): 16-23 ISSN 2220-6124 (online)
© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
s
MINIREVIEWS
Pediatric lupus nephritis: Management update Rajiv Sinha, Sumantra Raut Rajiv Sinha, Division of Pediatric Nephrology, Department of Pediatrics, Institute of Child Health, Kolkata 700017, India Sumantra Raut, Department of Pediatrics, Dr B C Roy Post Graduate Institute of Pediatric Sciences, Kolkata 700054, India Author contributions: Sinha R designed the study; Raut S performed the search; Sinha R and Raut S wrote the paper. Correspondence to: Dr. Rajiv Sinha, MD, FRCPCH (UK) (CCT, UK), Division of Pediatric Nephrology, Department of Pediatrics, Institute of Child Health, 11 Biresh Guha Street, Kolkata 700017, India. [email protected] Telephone: +91-93-30819380 Fax: +91-33-22801525 Received: May 30, 2013 Revised: August 28, 2013 Accepted: March 3, 2014 Published online: May 6, 2014
tosus (cSLE) is a rare but severe autoimmune disease with multisystem involvement. Renal disease occurs in 50% to 75% of all cSLE patients and is a major cause of increased morbidity and mortality. Originally SLE nephritis was treated with steroids with a poor outcome which improved markedly with the introduction of cyclophosphamide, but at the cost of increased side effects which resulted in a further search for a less toxic, but equally effective regime. Here we discuss some newer drugs including immune-modulators and monoclonal antibodies in addition to azathioprine and mycophenolate mofetil, however, most of the evidence on these medications is restricted to adult literature and pediatric data are extrapolated from these trials.
Abstract
Sinha R, Raut S. Pediatric lupus nephritis: Management update. World J Nephrol 2014; 3(2): 16-23 Available from: URL: http:// www.wjgnet.com/2220-6124/full/v3/i2/16.htm DOI: http:// dx.doi.org/10.5527/wjn.v3.i2.16
Childhood-onset systemic lupus erythematosus (cSLE) is a severe multisystem autoimmune disease. Renal involvement occurs in the majority of cSLE patients and is often fatal. Renal biopsy is an important investigation in the management of lupus nephritis. Treatment of renal lupus consists of an induction phase and maintenance phase. Treatment of childhood lupus nephritis using steroids is associated with poor outcome and excess side-effects. The addition of cyclophosphamide to the treatment schedule has improved disease control. In view of treatment failure using these drugs and a tendency for non-adherence, many newer agents such as immune-modulators and monoclonal antibodies are being tried in patients with cSLE. Trials of these novel agents in the pediatric population are still lacking making a consensus in the management protocol of pediatric lupus nephritis difficult.
INTRODUCTION Epidemiology Childhood-onset systemic lupus erythematosus (cSLE) is a rare but severe autoimmune disease with multisystem involvement, the incidence is 0.3/100000-0.9/100000 children-per year with a prevalence of 3.3/100000-8.8/100000 children[1]. A higher frequency of cSLE is reported in Asians, African Americans, Hispanics, and native Americans[2]. Median age of onset of cSLE is between 11 and 12 years (rare below 5 years), and 80% of patients are female[3]. cSLE follows a more severe disease course than adult-onset SLE, with higher morbidity and lower survival rates[4].
© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
Diagnosis of cSLE Four out of 11 American College of Rheumatology (ACR) criteria have a sensitivity and specificity greater than 95% for the diagnosis of cSLE. These criteria are as follows: malar rash, discoid rash, photosensitivity rash, oral or nasopharyngeal ulceration, nonerosive arthritis,
Key words: Pediatric; Lupus nephritis; Management; Monoclonal antibody; Cyclophosphamide; Mycophenolate mofetil Core tip: Childhood-onset systemic lupus erythema-
WJN|www.wjgnet.com
16
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis [11,12]
Table 1 International society of nephrology/renal pathology society 2003 classification of lupus nephritis Class
Name Minimal mesangial LN Mesangial proliferative LN
I II III
Focal LN
IV
Diffuse LN
V VI
A Active lesions A/C Active and chronic lesions C Chronic lesions A Active lesions A/C Active and chronic lesions C Chronic lesions Membranous LN Advanced sclerosing LN
Light microscopy
Immunofluorescence
Normal Mesangial immune deposits Mesangial hypercellularity or mesangial Mesangial immune deposits matrix expansion Segmental, or global glomerulonephritis Diffuse subendothelial immune deposits (< 50% of glomeruli) Segmental, or global glomerulonephritis Diffuse subendothelial immune deposits LN (> 50% glomeruli) Global or segmental subepithelial immune deposits LN (> 90% globally Sclerosed glomeruli without residual activity)
Class V may occur in combination with class III or IV, in which case both will be diagnosed. LN: Lupus nephritis.
serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and antinuclear antibody[5]. Although still not widely used, the newer systemic lupus international collaborating clinics (SLICC) criteria have been introduced for the classification of SLE[6]. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-doublestranded DNA antibodies.
INDICATIONS FOR RENAL BIOPSY IN PATIENTS WITH CSLE[12] Increased serum creatinine without compelling alternative causes, such as sepsis, hypovolemia, or medication. Confirmed proteinuria of 1.0 g per 24 h (either 24-h urine specimens or spot protein/creatinine ratios are acceptable). Combinations of the following, assuming the findings are confirmed in at least 2 tests performed within a short period of time and in the absence of alternative causes: (1) Proteinuria: 0.5 g per 24 h plus hematuria, defined as 5 RBCs per hpf; and (2) Proteinuria: 0.5 g per 24 h plus cellular casts. Renal biopsy should be reported as per the International Society of Nephrology/Renal Pathology classification (Table 1). Recent modifications of the activity and chronicity index not only help in acute management, but also help in prognostication.
Renal involvement Renal disease occurs in 50% to 75% of all cSLE patients, mostly within the first 2 years after diagnosis[7]. Lupus nephritis (LN) is more common in males and in nonWhite populations[8,9]. Initial manifestations of renal disease range from minimal proteinuria and microscopic hematuria to nephrotic-range proteinuria, urinary casts, severe hypertension, peripheral edema, and renal insufficiency or acute renal failure. SLE most commonly affects the glomerulus (i.e., lupus nephritis), but can also involve the renal interstitium. It can also present with features of thrombotic microangiopathy including both atypical hemolytic uremic syndrome as well as thrombotic thrombocytopenic purpura.
TREATMENT Originally SLE nephritis was treated by steroids with a poor outcome which improved markedly with the introduction of cyclophosphamide. The first controlled trial reporting the short-term efficacy of cyclophosphamide for lupus nephritis in adults was published in 1971[13]. Initially this combination was advocated for a prolonged period, but unfortunately the improved outcome was found to be associated with long-term side effects, which resulted in a further search for a less toxic, but equally effective regime. Most of the studies have been performed in adults and to a large extent the current recommendations are borrowed heavily from adult studies. The current therapeutic strategy for SLE nephritis distinguishes two distinct phases of treatment. The first phase is INDUCTION therapy which aims to control disease activity by inducing remission of disease flare (which may be the initial presentation or represent a new flare). It is at this point that potential organ-threatening and/or life-
CASE DEFINITION FOR LN As per the ACR criteria, LN is defined as: persistent proteinuria i.e., 0.5 g per day [a spot urine protein/creatinine ratio of 0.5 can be substituted) or greater than 3+ by dipstick; and/or cellular casts including red blood cells (RBCs), granular, tubular, or mixed][10]. An additional, perhaps optimal, criterion is a renal biopsy sample demonstrating immune complex-mediated glomerulonephritis compatible with LN[11]. As the severity of the nephritis may not correlate with the severity of the clinical signs and symptoms, a renal biopsy should be performed for any suspicion of glomerulonephritis, including persistent mild proteinuria.
WJN|www.wjgnet.com
17
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
threatening disease needs to be aggressively treated. The second phase is MAINTENANCE, wherein the target is to avoid relapses and control the disease by limiting inflammation and damage. Class Ⅰ/Ⅱ LN are milder and generally do not require immunosuppressive treatment, whereas class Ⅲ /Ⅳ needs to be treated aggressively[14]. Research studies over the last decade have shown increasing evidence of the efficacy of mycophenolate mofetil (MMF)/azathioprine (AZA) with a better side effect profile as compared to cyclophosphamide (CyC). Despite this, as shown by the recently conducted consensus meeting of pediatric rheumatologists and nephrologists in North America, the majority still prefer CyC as the induction agent[15]. Most of the studies on the use of MMF in children have only been case series. The largest series included 31 children or young people who were treated with MMF (either initially or switched from AZA) and showed that 73% had a good response without any recorded major side-effects [16]. Among the multiple adult studies, the first comparative study on MMF compared with CyC was published in Hong Kong in 2000[17]. MMF and CyC showed similar rates of improvement and of complete remission, 81% and 76%, respectively. Patients experienced fewer sideeffects with MMF treatment. Subsequently Contreras et al[18], studied 59 adults with lupus nephritis who were initially treated with 4-7 mo infusions of CyC and then randomized to quarterly infusions of CyC or oral MMF or AZA. Patients treated with AZA or MMF showed fewer flares than those treated with CyC, six, three, and eight flares, respectively. Patients treated with MMF experienced fewer side-effects than those treated with CyC except for an increased risk of gastrointestinal symptoms and diarrhea with MMF. To date, the biggest study, the aspreva lupus management study (ALMS) attempted to determine the efficacy of MMF as an induction agent for LN. The study included 370 patients with class Ⅲ through Ⅴ lupus nephritis[19] and consisted of one 24-wk induction phase and thereafter a 3-year maintenance phase. The results did not show any difference between the percentages of patients responding to treatment (56.2% in the MMF group, and 53.0% in the CyC group). There was also no significant difference in the rate of side-effects and a tendency for more severe adverse events in the MMF group (P = 0.07). In a sub-analysis of the ALMS, Isenberg et al[20] showed that response varied with race, in that Black and Hispanic patients responded better to MMF (60.4%) compared to CyC (38.5%), P = 0.03. In a recently published meta-analysis, Touma et al[21] looked at the cumulative evidence for MMF/CyC as induction treatment. Four trials with 668 patients were included and no difference in clinical efficacy was found between the two drugs. MMF did, however, show significantly less alopecia (RR = 5.77; 95%CI: 1.56-21.38), but other side-effects were not significantly different. Researchers have also studied patients with class Ⅴ nephritis (i.e., a membranous pattern on kidney biopsy) and found no differences between the MMF and CyC-treated groups[22]. Based on these studies, the ACR has published their recommendation on
WJN|www.wjgnet.com
SLE nephritis, albeit targeted primarily towards the adult population. ACR recommendation As per the ACR recent recommendation for class Ⅲ/Ⅳ LN, MMF and glucocorticoids (GC) can be used as induction agents for African-American and Hispanic patients, whereas Cyc and GC remain the first choice for White populations. MMF and GC are agents of choice in isolated class Ⅴ LN[10]. In mixed cases such as class V with Ⅲ or Ⅳ LN, the treatment should be similar to that for class Ⅲ/Ⅳ LN. Other induction modalities that can be tried in refractory cases include intravenous immunoglobulin, plasma exchange and B-lymphocyte depletion agents such as Rituximab[23,24] (Figures 1 and 2). The ACR recommends either MMF or AZA and low dose steroid for the maintenance phase. MMF has been shown to be statistically better than AZA in terms of time to treatment failure (a composite including death, end stage renal disease, doubling of serum creatinine, and renal flare)[25]. In patients who fail to respond after 6 mo of treatment with GC plus MMF or CyC, the ACR recommend a switch of immunosuppressive agent from either CyC to MMF or from MMF to CyC, and these changes are accompanied by Ⅳ pulses of GCs. Adherence Non-adherence to immunosuppressive agents can be common in the adolescent age group[14], resulting in relapse of symptoms and sometimes an acute presentation with renal failure after initial successful treatment. Intravenous agents, such as CyC or rituximab can be considered in this situation, to ensure adherence and disease control.
RECENT ADVANCES IN SLE MEDICATIONS Despite advances in treatment, mortality related to SLE nephritis has been static over the last decade and morbidity continues to be a major factor. Hence, there is a strong need for more effective drugs with, if possible, fewer side-effects. Studies are particularly required in children, as due to a lack of pediatric studies drugs trialed on adults are still been tried in children with severe lupus nephritis. We will discuss some of the newer medicines, however, most of the evidence on these medications is restricted to adult literature. Rituximab Rituximab, a chimeric antibody targeting CD20-positive cells, was first used by Tullus[26] in 2000 in a girl with class Ⅴ lupus nephritis and therapy-resistant nephrotic syndrome. The therapeutic response was remarkable and her proteinuria improved so much that her serum albumin normalized. Many other clinicians have had similar clinical experiences and several case series have published positive results[14,27]. Unfortunately the first randomized
18
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
MMF 2-3 g/d × 6 mo (preferred to CYC in Hispanics and African American) plus GC i.v. pulse × 3 d then prednisolone 0.5-1.0 mg/kg per day, tapered after a few weeks to lowest effective dose (1 mg/kg per day if crescent seen)
CYC plus GC i.v. pulse × 3 d then prednisolone 0.5-1 mg/kg per day, tapered after a few weeks to lowest effective dose (1 mg/kg per day if crescent seen)
or
Low dose CYC 500 mg i.v. every 2 wk × 6 mo Followed by maintenance with oral MMF or AZA (White European)
6 mo
or
High dose CYC 2 500-1000 mg/m BSA i.v. every month × 6
Not improved
Improved
6 mo Improved MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
Improved
Maintenance MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
CYC (low/high) + pulse GC then daily GC
Not improved
MMF 1-2 g/d or AZA 2 mg/kg per day +/low dose daily GC
Not improved
Improved
Maintenance MMF 1-2 g/d or AZA 2 mg/kg per day +/- low dose daily GC
Rituximab or calcineurin inhibitors + GC
MMF 2-3 g/d × 6 mo + Pulse GC then daily GC
Not improved
Rituximab or calcineurin inhibitors + GC
Figure 1 Class Ⅲ/Ⅳ lupus nephritis induction therapy. MMF: Mycophenolate mofetil; CYC: Cyclophosphamide; GC: Glucocorticoids; iv: Intravenous; AZA: Azathioprine; BSA: Body surface area.
ing. A phase Ⅲ randomized double-blind placebo controlled study showed significant benefit, but to date, there is not enough data to recommend its use in children with lupus nephritis[31].
controlled trial, EXPLORER, which included 237 patients with moderate to severe extra-renal lupus did not find any difference between rituximab and placebo[28]. Another large randomized placebo-controlled study on rituximab, the LUNAR trial[29], which included 144 patients with class Ⅲ or Ⅳ lupus nephritis showed that only 30.6% of the patients in the placebo group and 25.4% of the rituximab-treated patient fulfilled the criteria for a complete response. Greater improvements in complement levels (P = 0.025) and antibodies to dsDNA (P = 0.007) were recorded in the rituximab group compared to the placebo group[30].
Ocrelizumab Ocrelizumab is a fully humanized antibody that targets CD20-positive B cells. It is a “next-generation rituximab” and the potential problem of human anti-chimeric antibody development is hopefully ameliorated. The BELONG study, 2010 was set up to study the efficacy of ocrelizumab in 381 patients with lupus nephritis[32] and the results are awaited.
Belimumab Belimumab is a fully humanized monoclonal antibody that binds to soluble B-lymphocyte stimulator (BLyS) and acts as a specific inhibitor of its biological activity. BLyS, also known as B-cell activating factor (BAFF) is an immunomodulatory cytokine that promotes B-cell survival, B-cell differentiation, and immunoglobulin class switch-
WJN|www.wjgnet.com
Epratuzumab Epratuzumab is a monoclonal antibody against CD22, another B-cell-specific surface antigen. Early open data in a few patients have shown positive results[33]. A study involving 227 patients found that a dose of 600 mg weekly was associated with greater british isles lupus activity
19
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis Figure 2 Treatment of class Ⅴ without proliferative changes and with nephrotic range proteinuria (> 3 g/24 h). MMF: Mycophenolate mofetil; AZA: Azathioprine; CYC: Cyclophosphamide; GC: Glucocorticoids.
MMF 2-3 g/d × 6 mo plus prednisolone 0.5-1 mg/kg per day × 6 mo
Improved
Not improved
2
MMF 1-2 g/d or AZA 2 mg/kg per day
CYC 500-1000 mg/m BSA i.v. every month × 6 plus GC pulse followed by prednisolone 0.5-1.0 mg/kg per day
Table 2 Monitoring schedule for systemic lupus erythematosus nephritis Stage of disease Active nephritis at onset of treatment Previous active nephritis, none currently No prior or current nephritis
Blood pressure
Urinalysis
1 3 3
1 3 6
Protein/creatinine ratio Serum creatinine 1 3 6
grading improvement[34].
C3/C4 level
Anti-DNA
2 3 6
3 6 6
1 3 6
Index scores (Safety of estrogens in lupus erythematosus national assessment) were given three infusions of two different doses of rigerimod or placebo followed by 12 wk of observation. The treatment seemed to be well tolerated and a statistically significant reduction in disease activity was recorded[38]. Longer-term studies are needed.
Tocilizumab Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor. In a phase Ⅰ study of 16 patients with mild to moderate lupus, tocilizumab was found to be well tolerated, significantly reducing plasma cells and dsDNA suggesting a good clinical response[35]. Further studies seem warranted.
Abatacept Abatacept is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7 which selectively modulates the CD80/CD86:CD28 co-stimulatory signal. A recent 12-mo double-blind placebo-controlled study in 118 lupus patients failed to meet the primary end point of a reduction in new flares[39]. Serious adverse events were higher in the abatacept group compared with the placebo group (20% vs 7%).
Abetimus Abetimus is an immunomodulating agent designed to induce tolerance in B cells directed against dsDNA and to reduce anti-dsDNA levels. It is a synthetic molecule consisting of four double-stranded oligodeoxyribonucleotides attached to non-immunogenic polyethylene glycol. Abetimus works through the formation and clearance of drug antibody complexes and by tolerating anti-dsDNA specific B cells. Cardiel et al[36], 2008 in a 22-mo study of 317 patients showed that abetimus failed to prolong time to flare compared to the placebo.
Infliximab The use of infliximab in lupus has been surrounded with major worries. Long-term use of infliximab in lupus patients can cause severe side-effects, including severe infections and even cerebral lymphoma[40].
Atacicept Atacicept is a receptor analogue that binds both BAFF and a proliferation-inducing ligand to related members of the tumor necrosis factor superfamily. A phase Ⅱ study of atacicept showed a marked reduction in B cells and immunoglobulin levels and a short term side-effect profile similar to placebo[37].
ADJUNCTIVE TREATMENTS The ACR recommended that all SLE patients with nephritis be treated with a background of hydroxychloroquine (HCQ), unless there is a contraindication [11]. HCQ treatment may reduce the risk of renal damage and clotting events in SLE[41-43]. Medications to control high blood pressure (anti-hypertensive), fluid overload (diuretics), proteinuria (angiotensin converting enzyme inhibitors), hypercoagulability (aspirin or other anticoagulants) and lipid control (statins)[22,44,45] are mainstays of adjunc-
Rigeromid Rigerimod is a spliceosomal peptide that is recognized by CD4+ T cells from patients with lupus, but not from those with other autoimmune diseases. In a 12-wk study, 150 patients with lupus and high SLE Disease Activity
WJN|www.wjgnet.com
[10]
20
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
tive treatment. Dietary restriction may be necessary in terms of sodium, protein and calories. Unlike adults, these recommendations must be adjusted to take into account the growth and developmental status of the child. Infection is the most common cause of death in cSLE due to immune suppression[46]. Infections can be difficult to differentiate from a flare of SLE disease activity. C-reactive protein monitoring can be useful as most SLE patients have normal levels, except during inter-current infections.
7 8
RECOMMENDED MONITORING OF LUPUS NEPHRITIS
9
SLE is a chronic disease with the possibility of frequent flare-ups. Hence, these children need to be followed up regularly (Table 2). Compliance can be a major issue and needs to be addressed during each clinic visit[47].
10 11
CONCLUSION In conclusion, the outcome of lupus nephritis is primarily dependent on histological classification at presentation. Early renal biopsy in all children with features of lupus nephritis to decide on induction therapy, aggressive treatment of hypertension and other adjunct therapy is recommended to improve mortality and morbidity of such patients.
12
REFERENCES 1
2
3
4
5
6
Kamphuis S, Silverman ED. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol 2010; 6: 538-546 [PMID: 20683438 DOI: 10.1038/ nrrheum.2010.121] Malleson PN, Fung MY, Rosenberg AM. The incidence of pediatric rheumatic diseases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 1996; 23: 1981-1987 [PMID: 8923379] Huang JL, Yao TC, See LC. Prevalence of pediatric systemic lupus erythematosus and juvenile chronic arthritis in a Chinese population: a nation-wide prospective populationbased study in Taiwan. Clin Exp Rheumatol 2004; 22: 776-780 [PMID: 15638056] Baqi N, Moazami S, Singh A, Ahmad H, Balachandra S, Tejani A. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol 1996; 7: 924-929 [PMID: 8793802] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725 [PMID: 9324032 DOI: 10.1002/art.1780400928] Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sánchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G, Magder LS. Derivation and validation of
WJN|www.wjgnet.com
13
14 15
16
17
18
21
the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677-2686 [PMID: 22553077 DOI: 10.1002/ art.34473] Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am 2012; 59: 345-364 [PMID: 22560574] Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, Urowitz M, Fortin PR, Petri M, Barr S, Gordon C, Bae SC, Isenberg D, Zoma A, Aranow C, Dooley MA, Nived O, Sturfelt G, Steinsson K, Alarcón G, Senécal JL, Zummer M, Hanly J, Ensworth S, Pope J, Edworthy S, Rahman A, Sibley J, El-Gabalawy H, McCarthy T, St Pierre Y, Clarke A, RamseyGoldman R. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2550-2557 [PMID: 16868977 DOI: 10.1002/art.21955] Alarcón GS, McGwin G, Petri M, Reveille JD, RamseyGoldman R, Kimberly RP. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002; 11: 95-101 [PMID: 11958584 DOI: 10.1191/9612332lu155oa] Dooley MA, Aranow C, Ginzler EM. Review of ACR renal criteria in systemic lupus erythematosus. Lupus 2004; 13: 857-860 [PMID: 15580982 DOI: 10.1191/0961203304lu2023oa] Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64: 797-808 [PMID: 22556106 DOI: 10.1002/acr.21664] Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241-250 [PMID: 14747370 DOI: 10.1097/01. ASN.0000108969.21691.5D] Steinberg AD, Kaltreider HB, Staples PJ, Goetzl EJ, Talal N, Decker JL. Cyclophosphamide in lupus nephritis: a controlled trial. Ann Intern Med 1971; 75: 165-171 [PMID: 4104337 DOI: 10.7326/0003-4819-75-2-165] Marks SD, Tullus K. Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr 2010; 99: 967-974 [PMID: 20222881] Mina R, von Scheven E, Ardoin SP, Eberhard BA, Punaro M, Ilowite N, Hsu J, Klein-Gitelman M, Moorthy LN, Muscal E, Radhakrishna SM, Wagner-Weiner L, Adams M, Blier P, Buckley L, Chalom E, Chédeville G, Eichenfield A, Fish N, Henrickson M, Hersh AO, Hollister R, Jones O, Jung L, Levy D, Lopez-Benitez J, McCurdy D, Miettunen PM, Quinterodel Rio AI, Rothman D, Rullo O, Ruth N, Schanberg LE, Silverman E, Singer NG, Soep J, Syed R, Vogler LB, Yalcindag A, Yildirim-Toruner C, Wallace CA, Brunner HI. Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2012; 64: 375-383 [PMID: 22162255 DOI: 10.1002/acr.21558.] Kazyra I, Pilkington C, Marks SD, Tullus K. Mycophenolate mofetil treatment in children and adolescents with lupus. Arch Dis Child 2010; 95: 1059-1061 [PMID: 20810399 DOI: 10.1136/adc.2009.178608] Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343: 1156-1162 [PMID: 11036121 DOI: 10.1056/NEJM200010193431604] Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis Nan P, Roth D. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350: 971-980 [PMID: 14999109 DOI: 10.1056/NEJMoa031855] 19 Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20: 1103-1112 [PMID: 19369404 DOI: 10.1681/ ASN.2008101028] 20 Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, Sánchez-Guerrero J, Wofsy D, Yu X, Solomons N. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010; 49: 128-140 [PMID: 19933596 DOI: 10.1093/rheumatology/ kep346] 21 Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011; 38: 69-78 [PMID: 20952473 DOI: 10.3899/ jrheum.100130] 22 Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos II, Appel GB. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int 2010; 77: 152-160 [PMID: 19890271 DOI: 10.1038/ki.2009.412] 23 Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, Bonnet C, Cacoub P, Cantagrel A, de Bandt M, Fain O, Fautrel B, Gaudin P, Godeau B, Harlé JR, Hot A, Kahn JE, Lambotte O, Larroche C, Léone J, Meyer O, PallotPrades B, Pertuiset E, Quartier P, Schaerverbeke T, Sibilia J, Somogyi A, Soubrier M, Vignon E, Bader-Meunier B, Mariette X, Gottenberg JE. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010; 62: 2458-2466 [PMID: 20506527 DOI: 10.1002/art.27541] 24 Wright EC, Tullus K, Dillon MJ. Retrospective study of plasma exchange in children with systemic lupus erythematosus. Pediatr Nephrol 2004; 19: 1108-1114 [PMID: 15300476 DOI: 10.1007/s00467-004-1552-7] 25 Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365: 1886-1895 [PMID: 22087680 DOI: 10.1056/NEJMoa1014460] 26 Tullus K. New developments in the treatment of systemic lupus erythematosus. Pediatr Nephrol 2012; 27: 727-732 [PMID: 21516516 DOI: 10.1007/s00467-011-1859-0] 27 Marks SD, Tullus K. Targeted B-cell depletion therapy in childhood-onset systemic lupus erythematosus: progress to date. Paediatr Drugs 2007; 9: 371-378 [PMID: 18052407] 28 Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010; 62: 222-233 [PMID: 20039413 DOI: 10.1002/art.27233] 29 Furie R, Looney J, Rovin B, Latinis KM, Appel G, SanchezGuerrero J, Fervenza F, Maciuca RD, Brunetta P, Zhang D, Garg J, the LUNAR study group. Efficacy and safety of rituximab in patients with proliferative lupus nephritis: results from the randomized, double-blind phase III LUNAR study 2010. 9th International Congress on Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 6 30 Furie R, Rovin BH, Appel G, Kamen DL, Fervenza FC, Spindler A, Maciuca R, Garg JP, Brunetta P, LUNAR Study Group. Effect of rituximab on anti-double-stranded DNA antibody and C3 levels and relationship to response: results from the LUNAR trial 2010. 9th International Congress on
WJN|www.wjgnet.com
31
32
33
34 35
36
37
38
39
40
41
42
22
Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 22 Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, Ginzler EM, D’Cruz DP, Doria A, Cooper S, Zhong ZJ, Hough D, Freimuth W, Petri MA. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 2012; 71: 1833-1838 [PMID: 22550315 DOI: 10.1136/annrheumdis-2011-200831.] Mysler E, Spindler A, Guzman R, Bijl M, Jayne D, Furie R, Maciuca R, Drappa J, Shahdad S, Close D. Study design and baseline patient characteristics of BELONG, the randomized double-blind, placebo-controlled phase III trial of ocrelizumab, a humanized anti-CD20 antibody, in lupus nephritis 2010. 9th International Congress on Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 20 Dörner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 2006; 8: R74 [PMID: 16630358 DOI: 10.1186/ar1942] Press release, UCB, Rome 16th 2010; Available from: URL: http://www.ucb.com/_up/ucb_com_news/document. Accessed 10 Nov 2012 Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, Fleisher T, Balow JE, Lipsky PE. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010; 62: 542-552 [PMID: 20112381 DOI: 10.1002/art.27221] Cardiel MH, Tumlin JA, Furie RA, Wallace DJ, Joh T, Linnik MD. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum 2008; 58: 2470-2480 [PMID: 18668592 DOI: 10.1002/art.23673] Pena-Rossi C, Nasonov E, Stanislav M, Yakusevich V, Ershova O, Lomareva N, Saunders H, Hill J, Nestorov I. An exploratory dose-escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus. Lupus 2009; 18: 547-555 [PMID: 19395457 DOI: 10.1177/0961203309102803] D’Andrea D, Xie F, Zimmer R. A randomized, doubleblind, placebo-controlled study of spliceosomal peptide rigerimod in patients with systemic lupus erythematosus (SLE), 2010. 9th Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P. The efficacy and safety of abatacept in patients with non-lifethreatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62: 3077-3087 [PMID: 20533545 DOI: 10.1002/art.27601] Aringer M, Houssiau F, Gordon C, Graninger WB, Voll RE, Rath E, Steiner G, Smolen JS. Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients. Rheumatology (Oxford) 2009; 48: 1451-1454 [PMID: 19748965 DOI: 10.1093/rheumatology/kep270] A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N Engl J Med 1991; 324: 150-154 [PMID: 1984192 DOI: 10.1056/ NEJM199101173240303] Fessler BJ, Alarcón GS, McGwin G, Roseman J, Bastian HM, Friedman AW, Baethge BA, Vilá L, Reveille JD. Systemic lupus erythematosus in three ethnic groups: XVI. Association
May 6, 2014|Volume 3|Issue 2|
Sinha R et al . Pediatric lupus nephritis
43
44
of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 2005; 52: 1473-1480 [PMID: 15880829 DOI: 10.1002/art.21039] Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, Lou W, Fortin PR. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010; 62: 863-868 [PMID: 20131232 DOI: 10.1002/art.27289] Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148: 30-48 [PMID: 17984482 DOI: 10.7326/0003-4819-148-1-200801010-00190]
45
Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y, Shen P, Chen N. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012; 27: 1467-1472 [PMID: 21917733 DOI: 10.1093/ndt/gfr484] 46 Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, MartinezBerriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009; 11: R109 [PMID: 19604357 DOI: 10.1186/ar2764] 47 Schmajuk G, Yazdany J. Drug monitoring in systemic lupus erythematosus: a systematic review. Semin Arthritis Rheum 2011; 40: 559-575 [PMID: 21030066 DOI: 10.1016/j.semarthri t.2010.07.010] P- Reviewers: Martins LSS, Pedersen EB, Sheashaa HA, Tanaka H S- Editor: Gou SX L- Editor: Webster JR E- Editor: Wu HL
WJN|www.wjgnet.com
23
May 6, 2014|Volume 3|Issue 2|
Published by Baishideng Publishing Group Co., Limited Flat C, 23/F., Lucky Plaza, 315-321 Lockhart Road, Wan Chai, Hong Kong, China Fax: +852-31158812 Telephone: +852-58042046 E-mail: [email protected] http://www.wjgnet.com
Baishideng Publishing Group Co., Limited
© 2014 Baishideng. All rights reserved.
